The implantation site during early human pregnancy is characterized by extensive remodeling of the vasculature, invasion of fetal trophoblast cells, and by an abundance of maternal NK cells. The remodeling of the maternal vasculature, which occurs over the first twelve weeks of pregnancy, is essential to establish sufficient blood supply to the fetus. How NKtrophoblast cell interactions influence vascular remodeling is unknown. Invading trophoblast cells from the fetus express the non-classical major histocompatibility class I molecule HLA-G. It was long thought that the role of HLA-G was to inhibit maternal NK cells, which would otherwise attack the fetus. However, our work has led to a radically different understanding of the function of NK cells in pregnancy. We have identified KIR2DL4 (also known as CD158d) as the receptor for HLA-G. KIR2DL4 binds soluble HLA-G molecules and internalizes them into endosomal compartments inside NK cells. KIR2DL4 has the unique property of residing almost exclusively in endosomes. Endosomes are emerging as specialized signaling compartments that endow receptors with distinct signaling properties. The diversity of endosomal signaling pathways and their contribution to various biological responses is still unclear. Unlike other KIRs that mediate inhibition of NK cell cytotoxicity, KIR2DL4 triggers the production of a limited set of cytokines and chemokines. The profile of genes activated by KIR2DL4 carries a typical proinflammatory and proangiogenic signature. Two major questions raised by these findings are the mechanism for transport of KIR2DL4 to endosomes, and the signaling pathway triggered by KIR2DL4 once it is bound to soluble HLA-G within endosomes. By use of tandem affinity purification and mass spectrometry, we have identified a new signaling molecule associated with KIR2DL4 and elucidated the signaling pathway that links KIR2DL4 with the activation of a specific set of genes. KIR2DL4 bound to the serine/threonine kinase DNA-PKcs, which has an important role in DNA repair. However, in the context of KIR2DL4 signaling, DNA-PKcs promoted Akt recruitment to endosomes, and induced DNA-PKcs-dependent Akt phosphorylation. The sequential requirement for DNA-PKcs, Akt, and NF-kappaB in signaling by KIR2DL4 delineates a new endosomal signaling pathway for release of a unique set of proinflammatory and proangiogenic mediators in response to soluble HLA-G.